Diagnosis and management of pericardial effusion.

Pericardial effusion is a common finding in everyday clinical practice. The first challenge to the clinician is to try to establish an etiologic diagnosis. Sometimes, the pericardial effusion can be easily related to a known underlying disease, such as acute myocardial infarction, cardiac surgery, end-stage renal disease or widespread metastatic neoplasm. When no obvious cause is apparent, some clinical findings can be useful to establish a diagnosis of probability. The presence of acute inflammatory signs (chest pain, fever, pericardial friction rub) is predictive for acute idiopathic pericarditis irrespective of the size of the effusion or the presence or absence of tamponade. Severe effusion with absence of inflammatory signs and absence of tamponade is predictive for chronic idiopathic pericardial effusion, and tamponade without inflammatory signs for neoplastic pericardial effusion. Epidemiologic considerations are very important, as in developed countries acute idiopathic pericarditis and idiopathic pericardial effusion are the most common etiologies, but in some underdeveloped geographic areas tuberculous pericarditis is the leading cause of pericardial effusion. The second point is the evaluation of the hemodynamic compromise caused by pericardial fluid. Cardiac tamponade is not an "all or none" phenomenon, but a syndrome with a continuum of severity ranging from an asymptomatic elevation of intrapericardial pressure detectable only through hemodynamic methods to a clinical tamponade recognized by the presence of dyspnea, tachycardia, jugular venous distension, pulsus paradoxus and in the more severe cases arterial hypotension and shock. In the middle, echocardiographic tamponade is recognized by the presence of cardiac chamber collapses and characteristic alterations in respiratory variations of mitral and tricuspid flow. Medical treatment of pericardial effusion is mainly dictated by the presence of inflammatory signs and by the underlying disease if present. Pericardial drainage is mandatory when clinical tamponade is present. In the absence of clinical tamponade, examination of the pericardial fluid is indicated when there is a clinical suspicion of purulent pericarditis and in patients with underlying neoplasia. Patients with chronic massive idiopathic pericardial effusion should also be submitted to pericardial drainage because of the risk of developing unexpected tamponade. The selection of the pericardial drainage procedure depends on the etiology of the effusion. Simple pericardiocentesis is usually sufficient in patients with acute idiopathic or viral pericarditis. Purulent pericarditis should be drained surgically, usually through subxiphoid pericardiotomy. Neoplastic pericardial effusion constitutes a more difficult challenge because reaccumulation of pericardial fluid is a concern. The therapeutic possibilities include extended indwelling pericardial catheter, percutaneous pericardiostomy and intrapericardial instillation of antineoplastic and sclerosing agents. Massive chronic idiopathic pericardial effusions do not respond to medical treatment and tend to recur after pericardiocentesis, so wide anterior pericardiectomy is finally necessary in many cases.

Fatal myocardial rupture after acute myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALsartan In Acute myocardial iNfarcTion Trial (VALIANT).

BACKGROUND: Myocardial rupture is a relatively rare and usually fatal complication of myocardial infarction (MI). Early recognition of patients at greatest risk of myocardial rupture provides an opportunity for early intervention. METHODS: VALIANT was a double-blind, randomized, controlled trial comparing valsartan, captopril, and their combination in high-risk patients post-MI. Myocardial rupture was identified by autopsy (available in 138/589 patients dying within 30 days of index MI), echocardiography, direct surgical visualization, or presence of hemopericardium. An independent clinical end points committee reviewed medical records for all deaths or suspected nonfatal cardiovascular events. RESULTS: Rupture was identified in 45 (0.31%) patients enrolled in VALIANT, occurring 9.8 +/- 6.0 days after the qualifying MI. Rupture accounted for 7.6% (45/589) of all deaths occurring in the first 30 days of follow-up and 24% (33/138) of deaths in which autopsies were obtained. Compared with survivors, rupture was associated with increased age, hypertension, increased Killip class, lower estimated glomerular filtration rate, and Q wave MI, and inversely related to beta-blocker and diuretic use. Compared with patients who died of other causes within 30 days, patients with myocardial rupture were more likely to have had an inferior MI, Q wave MI, or hypertension; to have used oral anticoagulants; or to have received thrombolytic therapy. CONCLUSIONS: Although rare, myocardial rupture accounted for nearly one fourth of all deaths within the first 30 days after high-risk MI, suggesting an estimated incidence of approximately 1% within the first 30 days. A number of clinical characteristics may identify post-MI patients at higher risk of myocardial rupture.

Cardiologists' awareness and perceptions of guidelines for chronic heart failure. The ADDress your Heart survey.

BACKGROUND: Several surveys show that patients with chronic heart failure (CHF) are sub-optimally managed and treatment guidelines are not implemented in clinical practice. AIMS: To investigate awareness and perceptions of the 2005 European Society of Cardiology (ESC) guidelines for CHF. METHODS: 467 cardiologists from seven European countries completed an on-line interview using a validated, semi-structured questionnaire including questions about awareness and relevance of CHF guidelines. To assess agreement with ESC guidelines, three fictitious patient cases were presented and respondents' management choices compared with those of an expert panel based on the guidelines. RESULTS: Awareness of CHF guidelines was high, with 98% aware of any guideline and 65% aware of ESC guidelines. ESC guidelines were considered relevant (51%) or very relevant (38%) for guiding treatment decisions. Up to 92% of respondents perceived that they adhered to the ESC guidelines. For the patient cases,

Effect of clinical variables on the correlation between amount of ST elevation and myocardial scintigraphic perfusion defect during coronary occlusion.

PURPOSE: We investigated if the correlation between the amount of ST elevation (STE) and myocardial ischemia could be altered by variables such as hypertension or body mass index (BMI). METHODS: A 12-lead electrocardiogram and a technetium-99m tetrofosmin injection were performed during balloon coronary occlusion in 34 patients with single-vessel disease. RESULTS: The sum of STE correlated with scintigraphic extent of ischemia (r = 0.441; P = .009), but this correlation improved significantly in men and patients with BMI of 28 kg/m2 or less and was highest in nonhypertensive patients (r = 0.763; P < .001). In contrast, it was poor in women and patients with BMI greater than 28 kg/m2 or arterial hypertension, being lowest in the latter subset (r = 0.110; P = .664). Moreover, 8 (80%) of 10 patients with extensive hypoperfusion but with low SigmaSTE (< or =20 mm) were hypertensive. CONCLUSIONS: If confirmed by larger studies, electrocardiographic underestimation of transmural ischemia during coronary occlusion in patients with hypertension or increased BMI may lead to adjustments in STE criteria for reperfusion therapy.

Body mass index, prognosis and mode of death in chronic heart failure: results from the Valsartan Heart Failure Trial.

AIMS: To assess the relationship between body mass index (BMI), mortality and mode of death in chronic heart failure (CHF) patients; to define the shape of the relationship between BMI and mortality. METHODS AND RESULTS: We performed a post-hoc analysis of 5010 patients from the Valsartan Heart Failure Trial. The end-points of the study were all-cause and cardiovascular mortality. Mortality rate was 27.2% in underweight patients (BMI<22 kg/m2), 21.7% in normal weight patients (BMI 22-24.9 kg/m2), 17.9% in overweight patients (BMI 25-29.9 kg/m2) and 16.5% in obese patients (BMI>30 kg/m2) (p<0.0001). The rates of non-cardiovascular death did not differ among groups. The risk of death due to progressive heart failure was 3.4-fold higher in the underweight than in the obese patients (p<0.0001). Normal weight, overweight and obese patients had lower risk of death as compared with underweight patients (p=0.019, HR 0.76, 95% CI 0.61-0.96; p=0.0005, HR 0.68, 95% CI 0.55-0.84; p=0.003, HR 0.67, 95% CI 0.52-0.88, respectively) independently of symptoms, ventricular function, beta-blocker use, C-reactive protein and brain natriuretic peptide levels. CONCLUSIONS: In CHF patients a higher BMI is associated with a better prognosis independently of other clinical variables. The relationship between mortality and BMI is monotonically decreasing.

Low-pressure cardiac tamponade: clinical and hemodynamic profile.

BACKGROUND: Low-pressure cardiac tamponade is a form of cardiac tamponade in which a comparatively low pericardial pressure results in cardiac compression because of low filling pressure. This syndrome is poorly characterized because only isolated cases have been reported. We conducted a study of its clinical and hemodynamic profiles. METHODS AND RESULTS: From 1986 through 2004, we evaluated all patients at our institution with combined pericardiocentesis and cardiac catheterization. We identified those patients who fulfilled catheterization-based criteria of low-pressure cardiac tamponade and compared their clinical and catheterization data with those of patients with classic tamponade. A total of 1429 patients with pericarditis were evaluated, 279 of whom underwent combined pericardiocentesis and catheterization. Criteria of low-pressure cardiac tamponade were met in 29, whereas 114 had criteria of classic cardiac tamponade. Patients with low-pressure tamponade less frequently had clinical signs of tamponade, but the rate of constitutional symptoms, use of diuretics, and echocardiographic findings of tamponade were similar in both groups. Patients with low-pressure tamponade showed a significant increase in cardiac output after pericardiocentesis, but they usually had less severe cardiac tamponade compared with patients with classic tamponade. Prognosis was related mainly to the underlying disease. CONCLUSIONS: Low-pressure cardiac tamponade was identified in 20% of patients with catheterization-based criteria of tamponade. Clinical recognition may be difficult because of the absence of typical physical findings of tamponade in most patients. Although some patients are critically ill, most show a stable clinical condition. However, these patients obtain a clear benefit from pericardiocentesis.

Mitochondrial Ca2+ uptake during simulated ischemia does not affect permeability transition pore opening upon simulated reperfusion.

OBJECTIVE: Reenergization of ischemic cardiomyocytes may be associated with acute necrotic cell death due in part to cytosolic Ca2+ overload and opening of a permeability transition pore (PTP) in mitochondria. It has been suggested that Ca2+ overload during ischemia primes mitochondria for PTP opening during reperfusion. We investigated the ability of mitochondria to uptake Ca2+ during simulated ischemia (SI) and whether this uptake determines PTP opening and cell death upon simulated reperfusion (SR). METHODS: Rat heart mitochondria were submitted to either hypoxia (anoxic chamber) or to SI (respiratory inhibition, substrate depletion and acidosis) and subsequent SR. Mitochondrial Ca2+ uptake was monitored using Ca2+ microelectrodes after exposure to different [Ca2+] up to 25 microM during SI, and PTP opening was assessed by quantification of mitochondrial swelling (changes in absorbance rate at 540 nm) and calcein release. Mitochondrial Ca2+ uptake (Rhod-2 fluorescence) and cytosolic Ca2+ rise (Fura-2 ratio fluorescence) were further investigated in HL-1 cardiac myocytes submitted to SI/SR, and the effect of reducing mitochondrial Ca2+ load (with 25 microM ruthenium red) or blocking PTP opening (with 0.5 microM cyclosporin A) on the rate of cell death was investigated in adult cardiomyocytes exposed to SI/SR. RESULTS: SI induced a progressive dissipation of mitochondrial membrane potential (TMRE fluorescence); however, prior to the completion of depolarization, high levels of Ca2+ uptake were observed in mitochondria. SR induced PTP opening but this phenomenon was not influenced by the magnitude of mitochondrial Ca2+ uptake during previous SI. Blockade of the mitochondrial Ca2+ uniporter during SI in cardiomyocytes attenuated mitochondrial Ca2+ uptake but increased cytosolic Ca2+ overload and cell death upon subsequent SR. CONCLUSION: Mitochondrial Ca2+ uptake during SI buffers cytosolic Ca2+ overload but its magnitude appears not to be an important determinant of PTP opening upon subsequent SR.

Long-term outcome of surgically treated aortic regurgitation: influence of guideline adherence toward early surgery.

OBJECTIVES: The purpose of this study was to compare postoperative outcome in two groups of patients with chronic severe aortic regurgitation (AR): those operated on early and those operated on late according to the guidelines. BACKGROUND: The impact of earlier surgery for chronic severe AR as defined in guidelines has not been evaluated. METHODS: A total of 170 patients with chronic severe AR submitted to aortic valve replacement were prospectively followed up. Patients were divided in two groups depending on the clinical situation at the time of surgery. Group A were 60 patients who were operated on following guidelines advice of earlier surgery, and group B were 110 patients who were operated on late with regard to guideline recommendations. RESULTS: Follow-up was 10 +/- 6 years (1 to 22 years). During follow-up 44 patients died, 7 patients (12%) from group A and 37 (37%) from group B (p = 0.001). The cause of death was non-cardiac in 11 patients, 2 (3%) in group A and 9 (8%) in group B. Cardiac deaths occurred in 33 patients, 5 (9%) from group A and 28 (28%) from group B (p = 0.002). Causes of death differed between groups A and B: heart failure or sudden death were significantly more frequent in group B (20 patients vs. 1 patient, p = 0.001). Overall survival in groups A and B was 90 +/- 4% vs. 75 +/- 8% at 5 years, 86 +/- 5% vs. 64 +/- 5% at 10 years, and 78 +/- 7% vs. 53 +/- 6% at 15 years, respectively (p = 0.009). CONCLUSIONS: Early operation as defined in the guidelines improves long-term survival in patients with chronic AR.

Ischemic preconditioning prevents calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion.

OBJECTIVES: We previously demonstrated that ischemic preconditioning (IPC) attenuates calpain activation during reperfusion. Herein, we tested the hypothesis that enhancement of Na+/K+-ATPase activity during early reperfusion as a result of calpain inhibition is involved in the protection afforded by myocardial IPC. METHODS: Intracellular Na+ concentration ([Na+]i) measured using 23Na-magnetic resonance spectroscopy, Na+/K+-ATPase activity, detachment of Na+/K+-ATPase alpha subunits from the membrane cytoskeleton, degradation of fodrin and ankyrin, and calpain activation were analysed in isolated rat hearts reperfused after 60 min of ischemia with or without previous IPC and different treatments aimed to mimic or blunt the effects of IPC. RESULTS: In non-treated hearts subjected to ischemia (control hearts), reperfusion for 5 min severely reduced Na+/K+-ATPase activity and dissociated alpha1 and alpha2 subunits of Na+/K+-ATPase from the membrane-cytoskeleton complex in parallel with proteolysis of alpha-fodrin and ankyrin-B and calpain activation. IPC accelerated the recovery of [Na+]i, increased Na+/K+-ATPase activity, and prevented dissociation of Na+/K+-ATPase from the membrane-cytoskeleton complex. IPC also prevented alpha-fodrin and ankyrin-B loss and calpain activation, effects that were associated with attenuated lactate dehydrogenase (LDH) release and infarct size and improved contractile recovery. These effects of IPC were reproduced by perfusing the hearts with the calpain inhibitor MDL-28170 and by transient stimulation of cAMP-dependent protein kinase (PKA) with CPT-cAMP, and they were reverted by perfusing with the PKA inhibitor H89. CONCLUSION: The results of the present study are consistent with the hypothesis that enhanced recovery of Na+/K+-ATPase activity during reperfusion as a result of attenuated calpain-mediated detachment of the protein from the membrane-cytoskeleton complex contributes to the protection afforded by IPC.

Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine.

Increased mechanical tension in the ischemic region during acute coronary occlusion might favor the occurrence of phase Ib ventricular arrhythmias. We aimed to investigate whether intracoronary administration of Gd(3+), a stretch-activated channel blocker, into the ischemic zone reduces the incidence of these arrhythmias. In thiopental-anesthetized, open-chest pigs, the left anterior descending coronary artery (LAD) was ligated for 45 or 48 min. Phosphate-free, HEPES-buffered saline bubbled with 100% N(2) was infused into the ischemic region for 4 min, starting 5 min (series A; n = 16) or 20 min (series B; n = 16) after coronary occlusion, at a rate doubling the baseline blood flow. Animals were blindly allocated to receive 40 muM Gd(3+) or only the buffer during the final 2 min of the infusion. There were no differences between groups with respect to hemodynamic variables, plasma K(+) levels, or size of the ischemic region. In neither series was the number of phase Ib premature ventricular beats reduced by Gd(3+) (46 +/- 20 in untreated vs. 91 +/- 37 in Gd(3+)-treated animals in series A and 19 +/- 7 vs. 22 +/- 13, respectively, in series B; both P = not significant). The occurrence of ventricular tachycardia or fibrillation was significantly associated with the magnitude of early ischemic expansion of the LAD region, as measured by ultrasonic crystals, but was also not prevented by Gd(3+). These results argue against a major role of stretch-activated channels inside the area at risk in the genesis of phase Ib ischemic ventricular arrhythmias.

Protective effect of gap junction uncouplers given during hypoxia against reoxygenation injury in isolated rat hearts.

It has been shown that cell-to-cell chemical coupling may persist during severe myocardial hypoxia or ischemia. We aimed to analyze the effects of different, chemically unrelated gap junction uncouplers on the progression of ischemic injury in hypoxic myocardium. First, we analyzed the effects of heptanol, 18alpha-glycyrrhetinic acid, and palmitoleic acid on intracellular Ca2+ concentration during simulated hypoxia (2 mM NaCN) in isolated cardiomyocytes. Next, we analyzed their effects on developed and diastolic tension and electrical impedance in 47 isolated rat hearts submitted to 40 min of hypoxia and reoxygenation. All treatments were applied only during the hypoxic period. Cell injury was determined by lactate dehydrogenase (LDH) release. Heptanol, but not 18alpha-glycyrrhetinic acid nor palmitoleic acid, attenuated the increase in cytosolic Ca2+ concentration induced by simulated ischemia in cardiomyocytes and delayed rigor development (rigor onset at 7.31 +/- 0.71 min in controls vs. 14.76 +/- 1.44 in heptanol-treated hearts, P < 0.001) and the onset of the marked changes in electrical impedance (tissue resistivity: 4.02 +/- 0.29 vs. 7.75 +/- 1.84 min, P = 0.016) in hypoxic rat hearts. LDH release from hypoxic hearts was minimal and was not significantly modified by drugs. However, all gap junction uncouplers, given during hypoxia, attenuated LDH release during subsequent reoxygenation. Dose-response analysis showed that increasing heptanol concentration beyond the level associated with maximal effects on cell coupling resulted in further protection against hypoxic injury. In conclusion, gap junction uncoupling during hypoxia has a protective effect on cell death occurring upon subsequent reoxygenation, and heptanol has, in addition, a marked protective effect independent of its uncoupling actions.

Effects of hypoxia, glucose deprivation and acidosis on phosphatidylcholine synthesis in HL-1 cardiomyocytes. CTP:phosphocholine cytidylyltransferase activity correlates with sarcolemmal disruption.

A decrease in [3H]Cho (choline) incorporation in to PtdCho (phos-phatidylcholine) preceded the onset of LDH (lactate dehydrogenase) release in HL-1 cardiomyocytes submitted to simulated ischaemia. This observation led us to examine the role of PtdCho synthesis in sarcolemmal disruption in HL-1 cardiomyocytes. To address this objective we analysed the individual effects of hypoxia, glucose deprivation and acidosis, three prominent components of ischaemia, on the different steps of the Kennedy pathway for the synthesis of PtdCho. Pulse and pulse-chase experiments with [3H]Cho, performed in whole HL-1 cells submitted to hypoxia or normoxia, in the presence or absence of glucose at different pHs indicated first, that CK (choline kinase) was inhibited by hypoxia and acidosis, whereas glucose deprivation exacerbated the inhibition caused by hypoxia. Second, the rate-limiting reaction in PtdCho synthesis, catalysed by CCT (CTP:phosphocholine cytidylyltransferase), was inhibited by hypoxia and glucose deprivation, but unexpectedly activated by acidosis. In cellfree system assays, acidosis inhibited both CK and CCT. In experiments performed in whole cells, the effect of acidosis was likely to be direct on CK, but indirect or intact-cell-dependent on CCT. Since hypoxia and glucose deprivation favoured membrane disruption, but acidosis prevented it, we hypothesized that the modulation of CCT could be an important determinant of cell survival. Supporting this hypothesis, we show that CCT activity in whole-cell experiments clearly correlated with LDH release, but not with ATP concentration. Altogether our results suggest a significant role for CCT activity in sarcolemmal disruption during ischaemia.

Relation of myocardial perfusion defects and nonsignificant coronary lesions by angiography with insights from intravascular ultrasound and coronary pressure measurements.

Several studies have demonstrated a correlation between myocardial ischemia and severity of coronary lesions as determined by intravascular ultrasound (IVUS) and fractional flow reserve (FFR) measurements. However, their value for the assessment of mild coronary stenoses that are associated with myocardial perfusion abnormalities has not been well studied. The objective of this study was to prospectively compare the results of myocardial perfusion as determined by exercise/dipyridamole myocardial single-photon emission computed tomography with IVUS and FFR measurements in patients who had angiographically mild coronary stenosis (< 50% diameter stenosis by quantitative coronary angiography). Forty-eight patients who had stable coronary disease (61 +/- 11 years of age; 6 women) were included. All had mild coronary stenosis in the proximal/middle segment of > or = 1 coronary artery and had undergone maximal exercise myocardial technetium-99m tetrofosmin single-photon emission computed tomography within 48 hours before coronary angiography. IVUS measurements included lesion lumen area, external elastic membrane area, lesion plaque burden (calculated as external elastic membrane minus lumen area, divided by external elastic membrane, and multiplied by 100), and lumen area stenosis (calculated as reference lumen area minus lesion lumen area, divided by reference lumen area, multiplied by 100). Fifty-three coronary lesions were studied, with a mean percent diameter stenosis of 34.9 +/- 7.9% on angiography. Myocardial perfusion defects were demonstrated by single-photon emission computed tomography in 11 patients (12 myocardial regions) with no differences in lesion percent diameter stenosis compared with those without perfusion defects. The presence of reversible perfusion defects was associated with a higher lesion plaque burden as evaluated by IVUS (67.4 +/- 8.1% vs 60.2 +/- 9.3%, p = 0.01). FFR values did not differ in the presence or absence of perfusion defects (0.90 +/- 0.06 vs 0.92 +/- 0.07, respectively; p = NS). In conclusion, plaque burden as determined by IVUS may partly explain the presence of myocardial perfusion defects in cases of angiographically nonsignificant coronary lesions. However, the high FFR values associated with these lesions suggest that other mechanisms, such as endothelial/microvascular dysfunction, might also account for perfusion abnormalities in these patients.

Correspondence between left ventricular 17 myocardial segments and coronary arteries.

AIMS: The last guidelines recommend a standardized 17-segment model for tomographic imaging of the left ventricle. The aim of this study is to analyse the correspondence of the 17 left ventricular segments with each coronary artery by myocardial perfusion SPECT studies. METHODS AND RESULTS: Fifty patients selected for percutaneous revascularization of one coronary artery [24 left anterior descending (LAD), 15 right coronary artery (RCA), and 11 left circumflex (LCX)] were included. The (99m)Tc-labelled compound was injected immediately after the inflation of the balloon during percutaneous coronary angioplasty. At least 90 s of complete occlusion time was required. Maximal contour of regions of hypoperfusion corresponding to each coronary artery occlusion were delineated over the polar map of 17 segments. Nine segments corresponded to only one coronary artery: eight to LAD (basal anterior, basal anteroseptal, mid-anterior, mid-anteroseptal, apical anterior, apical septal, apical lateral, and apex) and one to LCX (basal anterolateral). Basal inferoseptal, mid-inferoseptal, and apical inferior segments could correspond to LAD or RCA. Basal inferior, basal inferolateral, mid-inferior, and mid-inferolateral segments could correspond to RCA or LCX, whereas the mid-anterolateral segment could correspond to LAD or LCX. CONCLUSION: The most specific segments (anterior, anteroseptal, and all apical segments except the infero-apical) correspond to LAD but no segment can be exclusively attributed to the RCA. Inferoseptal segments can be attributed to LAD or RCA, inferior and inferolateral segments to RCA or LCX, and mid-anterolateral segment to LAD or LCX.

Long-term vasodilator therapy in patients with severe aortic regurgitation.

BACKGROUND: Vasodilator therapy can reduce the left ventricular volume and mass and improve left ventricular performance in patients with aortic regurgitation. Accordingly, it has been suggested that such therapy may reduce or delay the need for aortic-valve replacement. METHODS: We randomly assigned 95 patients with asymptomatic severe aortic regurgitation and normal left ventricular function to receive open-label nifedipine (20 mg every 12 hours), open-label enalapril (20 mg per day), or no treatment (control group) to identify the possible beneficial effects of vasodilator therapy on left ventricular function and the need for aortic-valve replacement. RESULTS: After a mean of seven years of follow-up, the rate of aortic-valve replacement was similar among the groups: 39 percent in the control group, 50 percent in the enalapril group, and 41 percent in the nifedipine group (P=0.62). In addition, there were no significant differences among the groups in aortic regurgitant volume, left ventricular size, left ventricular mass, mean wall stress, or ejection fraction. One year after valve replacement, the left ventricular end-diastolic diameter and end-systolic diameter had decreased to a similar degree among the patients who underwent surgery in each of the three groups, and all the patients had a normal ejection fraction. CONCLUSIONS: Long-term vasodilator therapy with nifedipine or enalapril did not reduce or delay the need for aortic-valve replacement in patients with asymptomatic severe aortic regurgitation and normal left ventricular systolic function. Furthermore, such therapy did not reduce the aortic regurgitant volume, decrease the size of the left ventricle, or improve left ventricular function.

Calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion contributes to cell death after myocardial ischemia.

Na+ overload and secondary Ca2+ influx via Na+/Ca2+ exchanger are key mechanisms in cardiomyocyte contracture and necrosis during reperfusion. Impaired Na+/K+-ATPase activity contributes to Na+ overload, but the mechanism has not been established. Because Na+/K+-ATPase is connected to the cytoskeleton protein fodrin through ankyrin, which are substrates of calpains, we tested the hypothesis that calpain mediates Na+/K+-ATPase impairment in reperfused cardiomyocytes. In isolated rat hearts reperfused for 5 minutes after 60 minutes of ischemia, Na+/K+-ATPase activity was reduced by 80%, in parallel with loss of alpha-fodrin and ankyrin-B and detachment of alpha1 and alpha2 subunits of Na+/K+-ATPase from the membrane-cytoskeleton complex. Calpain inhibition with MDL-7943 during reperfusion prevented the loss of these proteins, increased Na+/K+-ATPase activity, attenuated lactate dehydrogenase release, and improved contractile recovery, and these beneficial effects of MDL-7943 were reverted by ouabain. The impairment of Na+/K+-ATPase was not a mere consequence of cell death because it was not altered in hearts in which contracture and cell death had been prevented by contractile blockade with 2,3-butanedione monoxime. In these hearts, concomitant calpain inhibition preserved Na+/K+-ATPase content and function and attenuated cell death occurring on withdrawal of 2,3-butanedione monoxime. In vitro assay showed no detectable degradation of Na+/K+-ATPase subunits after 10 minutes of incubation with activated calpain. Thus, we conclude that calpain activation contributes to the impairment of Na+/K+-ATPase during early reperfusion and that this effect is mainly mediated by degradation of the anchorage of Na+/K+-ATPase to the membrane cytoskeleton.

Acute cardiogenic pulmonary edema--relevance of multivessel disease, conduction abnormalities and silent ischemia.

The frequency distribution and severity of the cardiac disease underlying acute cardiogenic pulmonary edema (APE) to define appropriate subsequent diagnostic and management strategies were investigated in 216 consecutive patients. To this effect, the clinical, electrocardiographic, ecocardiographic and angiographic characteristics were analyzed. Coronary artery disease was identified in 185 patients (86%)-146 with acute myocardial infarction-as the underlying cause, isolated valvular disease in 10 (5%) and other causes in 21 (11%). Most patients were elderly (> or =70 years, 72%), hypertensive (71%) and diabetic (44%). Among coronary disease (CAD) patients, however, 105 (57%) showed conduction disturbances in the ECG (QRS>0.10 s) and 84 (45%) had no anginal pain during pulmonary edema. A 2D echocardiogram showed a 30% incidence of moderate-severe mitral regurgitation in coronary disease and non-coronary disease patients, and a 67% incidence of reduced ejection fraction (<50%), particularly in coronary disease patients (73%). A coronary angiography performed in 99 patients with coronary disease showed multivessel disease in 89 (91%) with a 32% incidence of significant left main disease. Therefore, these findings demonstrate that coronary disease is the most common cause of acute pulmonary edema and it is associated with a distinctly high prevalence of multivessel and left main disease. This diagnosis, however, may often be overlooked if no serial enzymatic sampling is performed given the increased frequency of conduction abnormalities and lack of anginal pain.